Autophagy: A new player in skeletal maintenance?

Abstract

Imbalances between bone resorption and formation lie at the root of disorders such as osteoporosis, Paget's disease of bone (PDB), and osteopetrosis. Recently, genetic and functional studies have implicated proteins involved in autophagic protein degradation as important mediators of bone cell function in normal physiology and in pathology. Autophagy is the conserved process whereby aggregated proteins, intracellular pathogens, and damaged organelles are degraded and recycled. This process is important both for normal cellular quality control and in response to environmental or internal stressors, particularly in terminally-differentiated cells. Autophagic structures can also act as hubs for the spatial organization of recycling and synthetic process in secretory cells. Alterations to autophagy (reduction, hyperactivation, or impairment) are associated with a number of disorders, including neurodegenerative diseases and cancers, and are now being implicated in maintenance of skeletal homoeostasis. Here, we introduce the topic of autophagy, describe the new findings that are starting to emerge from the bone field, and consider the therapeutic potential of modifying this pathway for the treatment of age-related bone disorders. ß

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

“…Similarly, rapamycin has been proven to be able to reduce the severity of age‐related bone changes in trabecular bone of older male rats by partially activating autophagy of osteocytes (Luo, Ren, Li, Lian, & Lin, 2016), which is consistent with our findings. Also, rapamycin has been reported to be able to inhibit osteoclast number and formation in experimental animal models and reduce bone resorption in patients (Hocking, Whitehouse, & Helfrich, 2012). Therefore, the beneficial effects of rapamycin might be coordinated by different bone cells.…”

Osteoporosis and autophagy: What is the relationship?

“…26,27,55 For example, cultures of autophagy gene-knockout osteoblasts (BECN-1, ATG7 e LC3) result in deficiency in the process of mineralization. 56 In vitro studies show that pharmacological inhibition of autophagy in osteoblast-like cells increases oxidative stress and stimulates apoptosis in these cells.…”

“…61 Osteocytes are long-lived cells located in gaps delimited by mineralized bone matrix and, consequently, are positioned in an environment more susceptible to hypoxia and to the accumulation of oxidative stress. 55 It is believed that under these conditions autophagy plays an important role in the survival of osteocytes. 59 Osteocyte-like cells have increased autophagic activity after undergoing nutrient deprivation and hypoxia in vitro, conditions that are similar to those found in osteocytes in vivo.…”

“…65 Some authors suggest that inhibition of autophagy in osteoclasts may serve as a possible therapeutic mechanism against bone diseases in which there is an excessive increase in bone resorption. 55,72 In fact, it has recently been observed in mice that pharmacological and genetic inhibition of autophagy reduces osteoclastogenesis and bone resorption, inhibiting bone loss caused by ovariectomy or glucocorticoid treatment. 74 Recently, autophagy has also been pointed as an important factor in the process of bone growth.…”

Autophagy protects osteoblasts from advanced glycation end products-induced apoptosis through intracellular reactive oxygen species

“…Autophagy plays a housekeeping role in eliminating old organelles, misfolded proteins, and damaged molecules; it also plays a role in recycling limited nutrients and oxygen (Hocking et al 2012). Autophagy is seen in all types of bone cells, and plays a complex and important role during osteogenesis (Carames et al 2010, Hocking et al 2012.…”